Diabetic retinopathy is characterized by increased permeability of the blood-retinal barrier and accelerated loss of retinal neurons through apoptotic cell death. Insulin is a known survival factor for endothelial and neural cells, and plays an important role in retinal function. Our preliminary work has demonstrated that insulin rescues retinal neuronal cells from apoptotic cell death, and systemic, intravitreal, and subconjunctival injections of insulin activate pro-survival insulin receptor and Akt kinases of diabetic rats. However, injected insulin has only temporary activities, and hypoglycemia limits the ability of patients to take enough insulin to minimize the risk of retinopathy. In designing clinical treatment for diabetic retinopathy, sustained release of insulin to the retina may augment effects of systemic insulin without risking hypoglycemia. The overall goal of this project is to develop novel drug delivery systems for long-term release of therapeutic agents for the prevention and treatment of diabetic retinopathy. The objective of this project is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin for at least two months to retard the development and progression of early experimental diabetic retinopathy. The central hypothesis underlying this project is that subconjunctivally implantable, biodegradable hydrogels can act as novel delivery systems for sustained delivery of insulin to protect retinal cells in diabetes. The two specific aims are: 1) In vitro optimization and characterization of thermo-responsive and biodegradable hydrogels for sustained release of insulin; and 2) In vitro and in vivo evaluation of the toxicity and efficacy of insulin-loaded, subconjunctivally implanted hydrogels on the retinal. This project is innovative, and will provide clinically relevant data on how to generate advanced biomaterials for controlled release of therapeutics including insulin, for treating diabetic retinopathy and other retinal disorders. It will also help us gain important insights into the mechanism of apoptotic cell death and increased vascular permeability in diabetes. Diabetic retinopathy is a potentially blinding complication of diabetes that damages the retina. The ocular drug delivery inventions of this translational research will provide effective and minimally invasive ocular therapy to prevent or treat early stages of diabetic retinopathy in Type 1 diabetes. [unreadable] [unreadable] [unreadable]